The Viral Epidemiology Branch (VEB) has used a variety of approaches to define the nature and magnitude of malignancies associated with HIV-1 and other chronic infections, including analyses of population-based data, prospective cohort studies, and laboratory investigations. We analyzed cancer incidence among 2992 subjects with CDC-defined AIDS (i.e., <200 CD4+ T-cells/ul) recruited in 1998-99. A total of 145 cases of cancer were observed during 7820 person-years of follow-up, corresponding to an annual cancer risk of 1.85%. Incidence of AIDS-defining cancers declined 50% by 2003/2004, while incidence of non-AIDS-defining cancers declined 30%. These cancers are being examined in nested case-control studies, utilizing the detailed clinical and interview data and banked blood specimens (plasma and cryopreserved lymphocytes) collected at enrollment. Antibody reactivity to HHV-8, the Kaposi's sarcoma (KS)-associated herpesvirus, was associated with 5 times greater risk of KS. Among HHV-8 seropositives, alcohol was additionally associated with increased KS risk. In contrast, cigarette smoking was protective both against HHV-8 antibody as well as against KS risk among HHV-8 seropositives. Alcohol and cigarettes each appear to have consistent effects at multiple stages of KS etiology, and further studies are planned to identify the underlying mechanisms. Non-AIDS-defining cancers are also important in this population, including lung cancer which accounted for 10% of cancer cases. All of the lung cancers occurred among current or former cigarette smokers, whereas one fourth of the cohort never smoked cigarettes. We have initiated an intensive laboratory investigation of non-Hodgkin's lymphoma (NHL)-associated mutations in these lymphocyte samples and their potential relationship to risk of NHL. Findings will be compared for HIV-related and unrelated NHL. Our two previous cohort studies of HIV-infected hemophilia patients have been incorporated into a larger cohort which includes HIV uninfecteds, whose prospective followup for cancer has recently been initiated. These cohorts will be applied to studies of potential risk factors for AIDS-related malignancy, including genetic polymorphisms and/or altered baseline levels of cytokines and other immune factors, chromosomal translocations, EBV and HHV-8 viral loads, antibody titers, and cell mediated immunity, novel viral co-factors, and environmental exposures and medications. We are continuing our studies of EBV infection and immune response as a causative factor in AIDS-related lymphoma, with determinations of viral load, cell-mediated immunity, antibody reactivity, and other immune system parameters. These studies also include examination of host genetic variation in B-cell-stimulatory cytokines. The Branch has also evaluated survival in lymphomas and other tumors using New York City data on 130,000 persons with HIV/AIDS through 2000. We found marked improvement in prognosis with improving antiretroviral therapies for the majority of AIDS and non-AIDS cancers, but gaps in survival remain between some tumors. Despite marked advances in antiretroviral therapy, cancer continues to be a major source of morbidity in AIDS.